Genetic Epidemiology of Glaucoma

Glaucoma is a heterogeneous group of optic neuropathies that have in common an accelerated degeneration of retinal ganglion cells and their axons, a subsequent typical excavation of the optic disc and a concomitant pattern of irreversible visual field loss. Glaucoma affects approximately 2% of individuals of European descent and up to 10% of individuals of sub-Saharan African descent over 50 years of age. It is a progressive disease, which without adequate treatment can result in severe visual disability and eventually blindness. Primary open-angle glaucoma (POAG) is the predominant form of glaucoma in Western countries. The disease is distinct from other forms of glaucoma through its age-related, insidious onset and an unobstructed iridocorneal angle with a normal appearance. Traditionally, an elevated intraocular pressure (IOP) was part of the clinical definition. However, an estimated 20 - 50% of all patients with otherwise characteristic POAG have IOPs consistently within the normal range (a condition referred to as “normal tension glaucoma”), whereas most individuals with an elevated IOP do not have any signs of glaucomatous optic neuropathy or visual field loss (a condition called “ocular hypertension”). Nevertheless, an elevated IOP is considered an important causative factor and the major risk factor for POAG. The 10-year incidence of glaucomatous visual field loss has been reported to increase by 11% [6-15%] per millimeter of mercury increase in IOP. Moreover, IOP is currently the only modifiable risk factor. Lowering the IOP, either by medication or surgically, has been shown to reduce the risk of conversion from ocular hypertension to glaucoma and to slow down the progression of glaucoma

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG.We performed a genome-wide association study of IOP in the population-based RotterdamStudy I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a newlocus associated with IOP. The most significantly associated SNPwas rs58073046 (ß = 0.44, P-value = 1.87 × 10-8, minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (ß = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10-8], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10-9; for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10-2). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12

Genetic architecture of open angle glaucoma and related determinants

Background Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG. Methods Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean +/- SD age: 64.6 +/- 9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean +/- SD age: 46.8 +/- 14.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control. Results The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG Conclusions We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a mode

A genetic epidemiologic study of candidate genes involved in the optic nerve head morphology

PURPOSE. The size of the optic nerve head, referred to as disc area (DA), and the vertical cup-disc ratio (VCDR), are clinically relevant parameters for glaucomatous optic neuropathy. Although these measures have a high heritability, little is known about the underlying genes. Previously, the genes SALL1 and SIX1 were found to be genome-wide significantly associated with DA and VCDR. The purpose of the present study was to investigate whether genes encoding protein known to interact with protein encoded by SALL1 and SIX1 are also associated with either DA or VCDR. METHODS. A total of 38 candidate genes were chosen covering all known proteins interacting with SALL1 and SIX1. These were initially studied in the Rotterdam Study (RS)-I, including 5312 Caucasian subjects characterized for DA and VCDR. Positive findings were further investigated in two independent cohorts (RS-II and RS-III) and finally replicated in a fourth population (ERF). Bonferroni correction was applied to the meta-analyses. RESULTS. Three loci were found to be associated with DA. The only locus significant after correcting for multiple testing is located on chromosome 11p13. Three single nucleotide polymorphisms (SNPs) in ELP4, a gene which neighbors and plays a crucial role in the expression of PAX6, show association in meta-analysis of the four cohorts yielding P values of respectively 4.79 × 10 -6, 3.92 × 10 -6, and 4.88 × 10 -6 which is below the threshold dictated by the most conservative Bonferroni correction (P = 5.2 × 10 -6). CONCLUSIONS. This study suggests that the ELP4-PAX6 region plays a role in the DA. Further research to confirm this finding is needed

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Ophthalmic researc

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10 '8 for rs6445055), two on chromosome 9 (P = 2.80 × 10 '11 for rs2472493 near ABCA1 and P = 6.39 × 10 '11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10 '11 for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG

Erratum: Atomic layer deposition of a MoS2 film (Nanoscale (2014) 6 (10584-10588))

10.1039/c4nr90076fNanoscale6221400